Mitochondrial ATP Synthase in Cardiac Biology and Disease

线粒体 ATP 合酶在心脏生物学和疾病中的作用

• 批准号: 10758687
• 负责人: Richard N Kitsis
• 金额: $ 2.05万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10758687
• 关键词: ATP Synthesis Pathway; Acceleration; Acute; Address; Adrenergic Agents; Adult; Biology; Cardiac; Cardiac Myocytes; Cells; Complement; Deterioration; Disease; EFRAC; Echocardiography; Exercise; Funding; Gene Deletion; Generations; Goals; Health; Heart failure; Human Resources; Hyperthyroidism; Isoproterenol; Knock-out; Knockout Mice; Mammalian Cell; Mediating; Mitochondria; Mitochondrial Proton-Translocating ATPases; Modeling; Mus; Pathologic; Pathway interactions; Performance; Phenotype; Physiological; Pregnancy; Protocols documentation; Rest; Running; Stimulus; Stress; Wild Type Mouse; Work; cardiac pacing; chronotropic; conditioning; heart function; mouse model; parent grant; pharmacologic; physiologic stressor; pressure; response; treadmill

We have created two independent mouse models of adult cardiomyocyte-specific mitochondrial ATP synthase deficiency: cardiomyocyte-specific ATP5L knockout (KO) mice and cardiomyocyte-specific ATP5J KO mice. Analysis of both models have shown that mice with ~90% depletion of the mitochondrial ATP synthase unexpectedly remain healthy with normal cardiac function for several weeks before transitioning to lethal heart failure with reduced ejection fraction (HFrEF). Studies in the parent grant are investigating the compensatory mechanisms that maintain cardiac function in the face of severe mitochondrial ATP synthase depletion in cardiomyocytes and the mechanisms that eventually mediate the transition to heart failure which, interestingly, do not appear to involve further deterioration of cardiac energetics. Given the traditional view that the mitochondrial ATP synthesis is essential to sustain energetics in mammalian cells – especially energy- demanding cells such as cardiomyocytes – it is surprising that ~10% of its usual levels in cardiomyocytes are adequate to sustain basal mouse health and cardiac function. Our results suggest that the full complement of mitochondrial ATP synthase in cardiomyocytes is not needed at rest. This observation raises the question as to how much of the mitochondrial ATP synthase is needed in cardiomyocytes to sustain cardiac function under more energetically demanding conditions, a question that could not be previously addressed without these mouse models. To answer this question, it is necessary to impose a physiological stress on the mice that increases the energetic demands of cardiomyocytes – but without simultaneously activating pathological stress pathways. We have chosen to use acute β-adrenergic stimulation with isoproterenol and, independently, acute exercise. A second objective of the Supplement is to deepen our baseline characterization of the ATP5J KO mice, which were generated by the candidate. The baseline characterization of the ATP5L KO mice is already complete. However, studies performed after the parent grant was funded, show that the ATP5J KO mice appear to have an accelerated phenotype. Hence, these mice need a thorough baseline characterization. Thus, the specific aims are: 1. To extend the baseline characterization of the cardiomyocyte-specific ATP5J knockout mice. 2. To assess the response of cardiomyocyte-specific ATP5L KO and ATP5J KO mouse lines to physiological stimuli that increase cardiomyocyte energetic demands. The scientific questions addressed in this Supplement are directly related to those of the parent grant and the resulting information will enhance our understanding of the findings of the parent grant. However, both the proposed work in the Supplement and the personnel required to perform it are distinct from that in the parent grant.

我们建立了两个独立的成年心肌细胞特异性线粒体ATP合酶小鼠模型 缺乏：心肌细胞特异性ATP 5L敲除（KO）小鼠和心肌细胞特异性ATP 5 J KO小鼠。 对两种模型的分析表明，线粒体ATP合酶缺失约90%的小鼠， 在转变为致命心脏病之前，意外地保持健康，心脏功能正常数周 射血分数降低（HFrEF）。对父母补助金的研究正在调查 在严重线粒体ATP合酶耗竭的情况下维持心脏功能的机制 心肌细胞和最终介导心力衰竭转变的机制，有趣的是， 似乎并不涉及心脏能量学的进一步恶化。鉴于传统观点认为 线粒体ATP的合成是维持哺乳动物细胞能量-特别是能量- 要求细胞，如心肌细胞-令人惊讶的是，在心肌细胞中约10%的正常水平， 足以维持小鼠的基本健康和心脏功能。我们的研究结果表明， 心肌细胞中的线粒体ATP合酶在休息时不需要。这一观察提出了一个问题， 心肌细胞需要多少线粒体ATP合酶来维持心脏功能， 更积极的要求条件，一个问题，不能以前解决没有这些 小鼠模型。为了回答这个问题，有必要对小鼠施加生理压力， 增加心肌细胞的能量需求-但不会同时激活病理性应激 途径。我们选择用异丙肾上腺素进行急性β肾上腺素能刺激， 锻炼的补充的第二个目标是深化我们对ATP 5 J KO的基线表征 小鼠，由候选人产生。ATP 5L KO小鼠的基线表征已经是 完成.然而，在父母资助后进行的研究表明，ATP 5 J KO小鼠似乎 有一个加速表型。因此，这些小鼠需要彻底的基线表征。因此 具体目标是：1.扩展心肌细胞特异性ATP 5 J敲除小鼠的基线表征。 2.为了评估心肌细胞特异性ATP 5L KO和ATP 5 J KO小鼠系对生理性心肌保护的反应， 增加心肌细胞能量需求的刺激。本补编所述的科学问题 与父母补助金直接相关，由此产生的信息将有助于我们了解 家长补助金的调查结果然而，补编中拟议的工作和所需人员 这是一个与父母不同的地方。